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• W1567625048 abstract "Clopidogrel is the standard antiplatelet therapy in patients with acute coronary syndrome or undergoing percutaneous coronary intervention [1Anderson J.L. Adams C.D. Antman E.M. Bridges C.R. Califf R.M. Casey Jr, D.E. Chavey 2nd, W.E. Fesmire F.M. Hochman J.S. Levin T.N. Lincoff A.M. Peterson E.D. Theroux P. Wenger N.K. Wright R.S. Smith Jr, S.C. Jacobs A.K. Adams C.D. Anderson J.L. Antman E.M. et al.ACC/AHA 2007 guidelines for the management of patients with unstable angina/non‐ST‐elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non‐ST‐Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine.J Am Coll Cardiol. 2007; 50: e1-157Crossref PubMed Scopus (1575) Google Scholar, 2King 3rd, S.B. Smith Jr, S.C. Hirshfeld Jr, J.W. Jacobs A.K. Morrison D.A. Williams D.O. Feldman T.E. Kern M.J. O’Neill W.W. Schaff H.V. Whitlow P.L. Adams C.D. Anderson J.L. Buller C.E. Creager M.A. Ettinger S.M. Halperin J.L. Hunt S.A. Krumholz H.M. et al.ACC/AHA/SCAI2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines.J Am Coll Cardiol. 2008; 51: 172-209Crossref PubMed Scopus (590) Google Scholar, 3Kushner F.G. Hand M. Smith Jr, S.C. King 3rd, S.B. Anderson J.L. Antman E.M. Bailey S.R. Bates E.R. Blankenship J.C. Casey Jr, D.E. Green L.A. Hochman J.S. Jacobs A.K. Krumholz H.M. Morrison D.A. Ornato J.P. Pearle D.L. Peterson E.D. Sloan M.A. Whitlow P.L. et al.2009 focused updates: ACC/AHA guidelines for the management of patients with ST‐elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2009; 54: 2205-41Crossref PubMed Scopus (1160) Google Scholar]. To exert its effect, clopidogrel has to be converted into an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes [4Simon T. Verstuyft C. Mary‐Krause M. Quteineh L. Drouet E. Méneveau N. Steg P.G. Ferrières J. Danchin N. Becquemont L. French Registry of Acute ST‐Elevation and Non‐ST‐Elevation Myocardial Infarction (FAST‐MI) InvestigatorsGenetic determinants of response to clopidogrel and cardiovascular events.N Engl J Med. 2009; 360: 363-75Crossref PubMed Scopus (1531) Google Scholar]. This metabolite subsequently inhibits ADP‐stimulated platelet activation and aggregation by irreversibly binding to platelet P2Y12 receptors. In clinical practice, the pharmacodynamic response to clopidogrel is variable, 20–30% of patients showing a low response to clopidogrel, in terms of inhibition of ADP‐induced platelet aggregation [5Snoep J.D. Hovens M.M. Eikenboom J.C. Van Der Bom J.G. Jukema J.W. Huisman M.V. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta‐analysis.Am Heart J. 2007; 154: 221-31Crossref PubMed Scopus (375) Google Scholar, 6Ben‐Dor I. Kleiman N.S. Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy.Am J Cardiol. 2009; 104: 227-33Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. Furthermore, such ‘low responders’ have a poorer clinical outcome after an acute coronary syndrome or percutaneous coronary intervention than patients not ‘resistant’ to clopidogrel [6Ben‐Dor I. Kleiman N.S. Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy.Am J Cardiol. 2009; 104: 227-33Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 7Combescure C. Fontana P. Mallouk N. Berdague P. Labruyere C. Barazer I. Gris J.C. Laporte S. Fabbro‐Peray P. Reny J.L. for the CLOVIS study groupClinical implications of clopidogrel non‐response in cardiovascular patients: a systematic review and meta‐analysis.J Thromb Haemost. 2010; 8: 923-33PubMed Scopus (119) Google Scholar]. The low responsiveness to clopidogrel appears to result from low exposure to its active metabolite [8Heestermans A.A. Van Werkum J.W. Schömig E. Ten Berg J.M. Taubert D. Clopidogrel resistance caused by a failure to metabolize clopidogrel into its metabolites.J Thromb Haemost. 2006; 4: 1143-5Crossref PubMed Scopus (27) Google Scholar, 9Erlinge D. Varenhorst C. Braun O.O. James S. Winters K.J. Jakubowski J.A. Brandt J.T. Sugidachi A. Siegbahn A. Wallentin L. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo.J Am Coll Cardiol. 2008; 52: 1968-77Crossref PubMed Scopus (183) Google Scholar, 10Wallentin L. Varenhorst C. James S. Erlinge D. Braun O.O. Jakubowski J.A. Sugidachi A. Winters K.J. Siegbahn A. Prasugrel achieves greater and faster P2Y12receptor‐mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin‐treated patients with coronary artery disease.Eur Heart J. 2008; 29: 21-30Crossref PubMed Scopus (437) Google Scholar, 11Brandt J.T. Payne C.D. Wiviott S.D. Weerakkody G. Farid N.A. Small D.S. Jakubowski J.A. Naganuma H. Winters K.J. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation.Am Heart J. 2007; 153: 66.e9-16Crossref PubMed Scopus (528) Google Scholar], and an adequate level of platelet inhibition may be achieved in ‘low‐responder’ patients by increasing the clopidogrel dose [12Aleil B. Jacquemin L. De Poli F. Zaehringer M. Collet J.P. Montalescot G. Cazenave J.P. Dickele M.C. Monassier J.P. Gachet C. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP‐02 (Vasodilator‐Stimulated Phosphoprotein‐02) randomized study.JACC Cardiovasc Interv. 2008; 1: 631-8Crossref PubMed Scopus (125) Google Scholar, 13Bonello‐Palot N. Armero S. Paganelli F. Mancini J. De Labriolle A. Bonello C. Lévy N. Maillard L. Barragan P. Dignat‐George F. Camoin‐Jau L. Bonello L. Relation of body mass index to high on‐treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention.Am J Cardiol. 2009; 104: 1511-15Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. However, although laboratory tests could be valuable in clinical practice, the complexity of the mechanisms underlying this characteristic has so far precluded the establishment of any approach for routinely distinguishing ‘low responders’. The variability in the responsiveness to clopidogrel involves both genetic and pharmacologic factors [14Sharma R.K. Reddy H.K. Singh V.N. Sharma R. Voelker D.J. Bhatt G. Aspirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting.Vasc Health Risk Manag. 2009; 5: 965-72Crossref PubMed Google Scholar]. Thus, polymorphism of the CYP 2C19 genotype is an important determinant of responsiveness to clopidogrel and subsequent cardiovascular events [4Simon T. Verstuyft C. Mary‐Krause M. Quteineh L. Drouet E. Méneveau N. Steg P.G. Ferrières J. Danchin N. Becquemont L. French Registry of Acute ST‐Elevation and Non‐ST‐Elevation Myocardial Infarction (FAST‐MI) InvestigatorsGenetic determinants of response to clopidogrel and cardiovascular events.N Engl J Med. 2009; 360: 363-75Crossref PubMed Scopus (1531) Google Scholar, 15Mega J.L. Close S.L. Wiviott S.D. Shen L. Hockett R.D. Brandt J.T. Walker J.R. Antman E.M. Macias W. Braunwald E. Sabatine M.S. Cytochrome p‐450 polymorphisms and response to clopidogrel.N Engl J Med. 2009; 360: 354-62Crossref PubMed Scopus (2147) Google Scholar, 16Shuldiner A.R. O’Connell J.R. Bliden K.P. Gandhi A. Ryan K. Horenstein R.B. Damcott C.M. Pakyz R. Tantry U.S. Gibson Q. Pollin T.I. Post W. Parsa A. Mitchell B.D. Faraday N. Herzog W. Gurbel P.A. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.JAMA. 2009; 302: 849-57Crossref PubMed Scopus (1272) Google Scholar]; consequently, the US Food and Drug Administration has recently changed the prescribing information for clopidogrel to highlight this point [17Plavix (Clopidogrel Bisulfate). Label information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf. Accessed 12 March 2010.Google Scholar, 18Ellis K.J. Stouger G.A. McLeod H.L. Lee C.R. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations.Pharmacogenomics. 2009; 10: 1799-817Crossref PubMed Scopus (79) Google Scholar]. However, the CYP 2C19 genotype is not the sole determinant of response to clopidogrel; other factors, such as body weight, variations in absorption of the drug, drug interactions and variations in platelet P2Y12 receptors, should also be taken into consideration [15Mega J.L. Close S.L. Wiviott S.D. Shen L. Hockett R.D. Brandt J.T. Walker J.R. Antman E.M. Macias W. Braunwald E. Sabatine M.S. Cytochrome p‐450 polymorphisms and response to clopidogrel.N Engl J Med. 2009; 360: 354-62Crossref PubMed Scopus (2147) Google Scholar, 19Aleil B. Léon C. Cazenave J.P. Gachet C. P2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring.J Thromb Haemost. 2009; 7: 1747-9Crossref PubMed Scopus (30) Google Scholar, 20Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use.Eur Heart J. 2009; 30: 1964-77Crossref PubMed Scopus (258) Google Scholar]. By providing a better reflection of in vivo plasma levels of the active metabolite of clopidogrel, platelet function tests may therefore represent a more appropriate means of assessing overall response to clopidogrel. Therefore, we performed a pharmacokinetic and pharmacodynamic study in healthy volunteers to investigate the relationship between the plasma concentrations of the active metabolite of clopidogrel and the results of various platelet function tests used in routine practice. The study population comprised eight healthy male Caucasian volunteers (18–35 years of age, 55–85 kg). This was an open‐label study, in which each subject received a single 600‐mg loading dose of clopidogrel orally (Plavix 75 mg; Sanofi Pharma Bristol‐Myers Squibb SNC, Paris, France). Blood was collected before and 1, 2, 4, 6 and 8 h after clopidogrel administration. All subjects gave written informed consent to the protocol, which was approved by the local Ethics Committee (Rhône‐Alpes Loire, France). The study was performed in accordance with the principles of the Declaration of Helsinki. Platelet aggregation was measured by light transmittance aggregometry (TA∼4V aggregometer; Sd‐Medical, Heillecourt, France). Platelet‐rich plasma was prepared from citrate‐anticoagulated blood by centrifugation (150 × g, 10 min), and maximum platelet aggregation (MPA), induced by 5 and 10 μmol L−1 ADP (final concentration), was measured. Maximum inhibition of platelet aggregation was expressed according to the formula ΔMPA = MPA0 – MPAt, in which MPAt was the MPA value at time t post‐dose, and MPA0 was the MPA value at baseline. Flow cytometric analysis of vasodilator‐stimulated phosphoprotein (VASP) phosphorylation was performed with a commercial kit (PLT VASP/P2Y12 Test Kit; Diagnostica Stago, Marseille, France) and an FACSVantage SE cytometer (Becton Dickinson, Franklin Lakes, NJ, USA); the platelet reactivity index (PRI) was calculated, and the results were expressed as ΔPRI, which was the difference between PRI value at baseline and PRI value at time t post‐dose. Concentrations of the active metabolite of clopidogrel were analyzed in plasma obtained from 5‐mL blood samples collected in EDTA, to which 25 μL of 2‐bromo‐3′‐methoxyacetophenone (500 mmol L−1 in acetonitrile) had been immediately added to stabilize this active metabolite. Blood samples were immediately centrifuged, and aliquots of plasma were stored at − 80 °C until analysis. The active metabolite was assayed with a validated liquid chromatography tandem mass spectrometry method and an appropriate standard as previously described [21Takahashi M. Pang H. Kawabata K. Farid N.A. Kurihara A. Quantitative determination of clopidogrel active metabolite in human plasma by LC‐MS/MS.J Pharm Biomed Anal. 2008; 48: 1219-24Crossref PubMed Scopus (115) Google Scholar]. The lower limit of quantification of this method is 0.8 ng mL−1. The total area under the plasma concentration–time curve from time zero to infinity (AUC0–∞) was estimated by a non‐compartmental analysis with a log‐linear trapezoidal method (r software, version 2.9.2; R Foundation for Statistical Computing, Vienna, Austria). The peak plasma concentration (Cmax) was read directly from the experimental data. The pharmacokinetic parameters varied substantially between the eight subjects receiving a single 600‐mg dose of clopidogrel. The Cmax of the active metabolite of clopidogrel ranged from 37 to 131 ng mL–1 (median: 79 ng mL–1); the respective value for AUC0–∞ was 65–244 ng mL−1 × h (median: 112 ng mL−1 × h). The pharmacodynamic response to 600 mg of clopidogrel also varied widely. The VASP data showed that inhibition of P2Y12 receptors at Cmax ranged from 15% to 86% (median: 53%). At 10 μmol L−1 ADP, maximum inhibition of platelet aggregation ranged between 51% and 74% (median: 61%). At 5 μmol L−1 ADP, the respective figures were 36% and 67% (median: 52%). The pharmacodynamic response to clopidogrel was related to the extent of exposure to its active metabolite: both Cmax and AUC0–∞ were significantly correlated with the results of platelet function tests, regardless of the type of test used (Fig. 1). For both parameters, higher correlation coefficients were obtained with flow‐cytometric VASP analysis (R = 0.79 and R = 0.84, respectively; P < 0.05) than with light transmittance aggregometry (R < 0.75). Concerning the latter, the highest correlation coefficients were obtained when ADP was used at the concentration of 5 μmol L−1 (R = 0.76 for Cmax and R = 0.78 for AUC0–∞) than when it was used at 10 μmol L−1 (R = 0.77 and R = 0.70, respectively). This study in healthy volunteers receiving a single 600‐mg dose of clopidogrel, evaluating the relationship between plasma concentrations of the active metabolite of clopidogrel, determined using a validated method, and the results of platelet function tests, confirmed that the VASP assay, which specifically evaluates P2Y12 receptor inhibition, is of greater value than light transmittance aggregometry for monitoring the biological activity of clopidogrel [6Ben‐Dor I. Kleiman N.S. Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy.Am J Cardiol. 2009; 104: 227-33Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 19Aleil B. Léon C. Cazenave J.P. Gachet C. P2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring.J Thromb Haemost. 2009; 7: 1747-9Crossref PubMed Scopus (30) Google Scholar]. This may not be surprising, as light transmittance aggregometry also reflects P2Y1 receptor‐mediated aggregation not inhibited by thienopyridines [10Wallentin L. Varenhorst C. James S. Erlinge D. Braun O.O. Jakubowski J.A. Sugidachi A. Winters K.J. Siegbahn A. Prasugrel achieves greater and faster P2Y12receptor‐mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin‐treated patients with coronary artery disease.Eur Heart J. 2008; 29: 21-30Crossref PubMed Scopus (437) Google Scholar, 22Bouman H.J. Parlak E. Van Werkum J.W. Breet N.J. Ten Cate H. Hackeng C.M. Ten Berg J.M. Taubert D. Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel.J Thromb Haemost. 2010; 8: 482-8Crossref PubMed Scopus (108) Google Scholar]. Concerning light transmittance aggregometry, the stronger aggregatory stimulus (i.e. ADP at 10 μmol L−1 vs. 5 μmol L) appeared to better differentiate individual sensitivity to platelet inhibition by clopidogrel [23Delavenne X. Basset T. Zufferey P. Mallouk N. Laporte S. Mismetti P. UPLC method for quantitation of clopidogrel active metabolite.J Sep Sci. 2010; 33: 1968-72Crossref Scopus (22) Google Scholar]. It is not known whether the dose of clopidogrel administered might affect the value of the tests evaluating the response to this drug: in this study, volunteers were treated with a loading dose of clopidogrel (600 mg), and this dose, which provides faster and better inhibition of platelet aggregation than lower doses, was shown to be associated with a lower rate of low response [24Gachet C. P2 receptors, platelet function and pharmacological implications.Thromb Haemost. 2008; 99: 466-72Crossref PubMed Scopus (243) Google Scholar]. The originality of these results is that platelet inhibition by clopidogrel was correlated with both Cmax and AUC0–∞, which is consistent with the fact that the active metabolite of clopidogrel irreversibly inhibits binding of ADP to P2Y12 receptors [4Simon T. Verstuyft C. Mary‐Krause M. Quteineh L. Drouet E. Méneveau N. Steg P.G. Ferrières J. Danchin N. Becquemont L. French Registry of Acute ST‐Elevation and Non‐ST‐Elevation Myocardial Infarction (FAST‐MI) InvestigatorsGenetic determinants of response to clopidogrel and cardiovascular events.N Engl J Med. 2009; 360: 363-75Crossref PubMed Scopus (1531) Google Scholar]. Previous studies have shown this correlation, but only with Cmax, probably because of the assay method for the active metabolite of clopidogrel [23Delavenne X. Basset T. Zufferey P. Mallouk N. Laporte S. Mismetti P. UPLC method for quantitation of clopidogrel active metabolite.J Sep Sci. 2010; 33: 1968-72Crossref Scopus (22) Google Scholar, 25Taubert D. Kastrati A. Harlfinger S. Gorchakova O. Lazar A. Von Beckerath N. Schömig A. Schömig E. Pharmacokinetics of clopidogrel after administration of a high loading dose.Thromb Haemost. 2004; 92: 311-16Crossref PubMed Google Scholar]. Indeed, in our study, the active metabolite of clopidogrel was assayed with a reference standard and a validated stabilization procedure based on two principles: first, as for all calibration curves used to measure plasma levels of a given drug, we should use the drug itself – in the same way, it is also crucial to use a calibration curve obtained with the active metabolite itself [21Takahashi M. Pang H. Kawabata K. Farid N.A. Kurihara A. Quantitative determination of clopidogrel active metabolite in human plasma by LC‐MS/MS.J Pharm Biomed Anal. 2008; 48: 1219-24Crossref PubMed Scopus (115) Google Scholar, 26Gurbel P.A. Bliden K.P. Hayes K.M. Yoho J.A. Herzog W.R. Tantry U.S. The relation of dosing to clopidogrel responsiveness and the incidence of high post‐treatment platelet aggregation in patients undergoing coronary stenting.J Am Coll Cardiol. 2005; 45: 1392-6Crossref PubMed Scopus (374) Google Scholar] rather than clopidogrel [23Delavenne X. Basset T. Zufferey P. Mallouk N. Laporte S. Mismetti P. UPLC method for quantitation of clopidogrel active metabolite.J Sep Sci. 2010; 33: 1968-72Crossref Scopus (22) Google Scholar, 25Taubert D. Kastrati A. Harlfinger S. Gorchakova O. Lazar A. Von Beckerath N. Schömig A. Schömig E. Pharmacokinetics of clopidogrel after administration of a high loading dose.Thromb Haemost. 2004; 92: 311-16Crossref PubMed Google Scholar]; and second, as described by Takahashi et al. [26Gurbel P.A. Bliden K.P. Hayes K.M. Yoho J.A. Herzog W.R. Tantry U.S. The relation of dosing to clopidogrel responsiveness and the incidence of high post‐treatment platelet aggregation in patients undergoing coronary stenting.J Am Coll Cardiol. 2005; 45: 1392-6Crossref PubMed Scopus (374) Google Scholar], owing to rapid inactivation of the metabolite (80% of the initial concentration is degraded within 10 min), it is necessary to effectively stabilize the metabolite in the blood sample in which it is to be assayed, in order to avoid an underestimation of active metabolite concentration. This explains why, after administration of the same 600‐mg dose of clopidogrel, plasma concentrations of the active metabolite ranged from 40 to 140 ng mL−1 in our study, as compared with only 5–35 ng mL−1 in a previous study using a different stabilization procedure [23Delavenne X. Basset T. Zufferey P. Mallouk N. Laporte S. Mismetti P. UPLC method for quantitation of clopidogrel active metabolite.J Sep Sci. 2010; 33: 1968-72Crossref Scopus (22) Google Scholar]. In conclusion, with the use of a reference standard and validated stabilization procedure to assay the plasma concentration of the active metabilite of clopidogrel, we have confirmed the relationship between these concentrations and the results of platelet function tests. The flow cytometric VASP assay may be a valuable platelet function test for monitoring responsiveness to clopidogrel and individually tailoring clopidogrel therapy in routine practice. Assay of plasma concentrations of the active metabolite of clopidogrel may be an alternative to platelet function tests, provided that a validated method is used. The authors state that they have no conflict of interest. This research has received funding support from the University Hospital of Saint‐Etienne, and was promoted by the University Hospital of Saint‐Etienne. The study group was as follows. Coordinating center: P. Garnier, A. Garcin, B. Deygas and S. Laporte. Laboratory test: X. Delavenne, N. Mallouk and M. Piot. Data management: C. Bernabe and C. Chauvet. Investigators: P. Garnier, V. Bost, F. Robert, K. Guillot and P. Mismetti." @default.
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• W1567625048 title "Is there really a relationship between the plasma concentration of the active metabolite of clopidogrel and the results of platelet function tests?" @default.
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